1. Field of the Invention
The present invention relates to aminopiperidine derivatives having integrin xcex1vxcex23 antagonistic activity and pharmaceuticals comprising the same.
2. Background Art
A signal transduction system is very important to organisms from the viewpoint of maintaining life and inheriting the life over to the next generation, specifically from the viewpoints of physiological significance, mechanisms for the regulation of gene expression and the like. It has recently been clarified that integrins, glycoprotein receptors which are involved in cell adhesion and penetrate cell membranes, are related, for example, to wound healing and hemostasis, phagocytosis, biophylaxis, and the construction of cytoskeletons and, in addition, as such are molecules for signal transduction. For this reason, in recent years, organic chemistry associated with integrins has suddenly become drawn attention from the viewpoint of pharmacology, as well as from the viewpoints of molecular biology and cell biology.
It is being elucidated that, while the conformation of integrins undergoes a dynamic and complicate change, integrins binds to various ligands to transmit signal in both intracellular and extracellular directions (Junichi Takagi et al., The 50th Annual Meeting of the Japan Society for Cell Biology, S5-1, 1997). T. A. Springer of Harvard Medical School has recently predicted that a certain activated integrin has a xcex2-propeller structure and binds to a ligand on the upper face of the xcex2-propeller (Proc. Natl. Acad. Sci. USA, 94, 65, 1997). This hypothesis was also supported by researchers in our country (Atsushi Irie et al., The 50th Annual Meeting of the Japan Society for Cell Biology, S5-2, 1997), and three-dimensional analysis on a molecular level associated with the activation of integrins, binding between integrins and ligands and the like has been initiated on a full scale.
Among them, integrin xcex1vxcex23 binds binds to various extracellular matrixes, that is, ligands deeply involved, for example, in biodynamics or the crisis of diseases, such as vitronectin, fibrinogen, fibronectin, osteopontin, thrombospondin, von Willebrand factors, and collagen, to form complexes. Accordingly, integrin xcex1vxcex23 is of special interest as a potential drug target. In fact, xcex1vxcex23 is expressed in a large amount in B cells, macrophages, monocytes, smooth muscle cells, activated endothelial cells and the like. Further, xcex1vxcex23 is known not to be strongly expressed in endothelial cells in a resting stage, but to be highly activated in the course of growth and infiltration, that is, in vascularization, wound healing, and inflamed sites. Further, the correlation between the frequency of expression of xcex1vxcex23 and the increase in infiltration of cancer has been observed in various cancer cells. On the other hand, a group of researchers at Scripps Research Institute in U.S.A. have clarified by advanced computer-assisted video imaging microscopy that microvascular expression of xcex1vxcex23 is observed during experimental middle cerebral artery occlusion and reperfusion in a baboon as a model (Y. Okada et al., Am. J. Pathol., 149, 37, 1996).
As described above, relationship of cell species, which express integrin xcex1vxcex23 in vivo, with xcex1vxcex23 activation stage, biophylaxis mechanism and the like has led to an expectation of clinical application of molecules having integrin xcex1vxcex23 antagonistic activity in various fields. In fact, compounds having integrin xcex1vxcex23 antagonistic activity are intended to be used clinically, and the results of animal tests on compounds having xcex1vxcex23 antagonistic activity in a wide range of diseases have been reported (S. S. Srivatsa et al., The 69th Annual Meeting of American Heart Association, 0231, 1996 (DuPont-Merck); J. F. Gourvest et al., The 18th Annual Meeting of The American Society for Bone and Mineral Research, p228, 1996 (Roussel-Hoechst); S. B. Rodan et al., The 18th Annual Meeting of The American Society for Bone and Mineral Research, M430, 1996 (Merck); T. L. Yue et al., The 70th Annual Meeting of American Heart Association, 3733, 1997 (SmithKline Beecham); A. L. Racanelli et al., The 70th Annual Meeting of American Heart Association, 3734, 1997 (DuPont-Merck); and W. S. Westlin, Conference of American IBC, Feb. 23, 1998 (Searle and Co.).
From the viewpoint of chemical structure, compounds having integrin xcex1vxcex23 antagonistic activity can be classified into antibodies, low-molecular peptide and compounds analogous thereto, and small molecules. All the antagonists are structurally related to the sequence of tripeptide RGD (arginine-glycine-aspartic acid) that are considered indispensable for recognition in the attachment of a ligand. Low-molecular peptides having antagonistic activity include disintegrins derived from venom of snakes and, in addition, cyclic peptides. One of them, GpenGRGDSPCA, has been reported to inhibit migration of smooth muscle cells and to block integrin xcex1vxcex23, thereby actually inhibiting neointima formation in rabbits (E. T. Choi et al., J. Vasc. Surg.,19, 125, 1994). On the other hand, the cyclic peptide containing BTD designed by a xcex2-turn mimic has been proved to strongly binds to xcex1vxcex23 receptors (M. Goodman et al., Bioorg. Med. Chem. Lett., 7, 997, 1997).
Several methods are known for designing small molecules through the utilization of the amino acid sequence of interest (RGD being used herein) as a key. For example, a peptide mimetic for constructing a new molecule based on the backbone of a peptide chain is generally known in the art. The concept of a new de novo design focused on the chemical structure and spatial configuration of amino acid side chains has been introduced for the first time early in the 1990s (R. Hirschman et al., J. Am. Chem. Soc., 115, 12550, 1993). An attempt to apply this approach to the design and synthesis of xcex1vxcex23 antagonists has already been initiated (K. C. Nicolaou et al., Tetrahedron, 53, 8751, 1997).
Up to now, small molecules having xcex1vxcex23 antagonistic activity are disclosedipn WO 9532710, WO 9637492, WO 9701540, WO 9708145, WO 9723451, WO 9723480, WO 9724119, WO 9726250, WO 9733887, WO 9736858, WO 9736859, WO 9736860, WO 9736861, WO 9736862, and EP 0796855. Low-molecular organic compounds having xcex1vxcex23 antagonistic activity are also disclosed in U.S. Pat. Nos. 5,843,906 and 5,852,210, WO 9737655, WO 9808840, WO 9818460, WO 981359, WO 9835949, WO 9846220, British Patent Nos. 2326609 and 2327672, WO 9843962, WO 9724336, WO 9830542, WO 9905107, EP 820988, EP 820991, EP 853084, and Bioorganic and Medicinal Chemistry, 6, 1185-1208 (1998), which were published after the priority date of the present application.
The present inventors have found that a certain group of derivatives have potent integrin xcex1vxcex23 antagonistic activity. The present inventors have also found that a certain group of derivatives have potent cell adhesion inhibitory activity. The present inventors have further found that a certain group of derivatives have potent GP IIb/IIIa antagonistic activity and human platelet aggregation inhibitory activity.
Accordingly, an object of the present invention is to provide a compound having integrin xcex1vxcex23 antagonistic activity, cell adhesion inhibitory activity, GP IIb/IIIa antagonistic activity, and/or human platelet aggregation inhibitory activity.
Another object of the present invention is to provide a therapeutic agent for treating a disease selected from the group consisting of integrin xcex1vxcex23-mediated diseases, diseases such that the inhibition of cell adhesion is effective for the treatment of said diseases, and diseases such that GP IIb/IIIa antagonistic action and/or platelet aggregation inhibitory action are effective for the treatment of said diseases, and an agent for inhibiting platelet aggregation.
The compounds according to the present invention are those represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
wherein
A represents a saturated or unsaturated five- to seven-membered heterocyclic group containing two nitrogen atoms, which heterocyclic group is optionally condensed with other saturated or unsaturated five- to seven-membered carbocyclic ring or heterocyclic ring to form a bicyclic group, which heterocyclic group and bicyclic group are optionally substituted by C1-6 alkyl, amino, C1-6 alkoxy, C1-6 alkoxycarbonyl, or aralkyl and the C1-6 alkyl, amino, C1-6 alkoxy, C1-6 alkoxycarbonyl, and aralkyl groups are optionally substituted by C1-6 alkyl or C1-6 alkoxy,
or a group represented by formula 
wherein
R1, R2, and R3, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, or nitrile, or R1 and R2 may together form group xe2x80x94(CH2)ixe2x80x94, wherein i is 4 or 5, or group xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
D represents  greater than NR4 wherein R4 represents a hydrogen atom or C1-6 alkyl which is optionally substituted by phenyl optionally substituted by C1-6 alkoxy;  greater than CR5R6 wherein R5 and R6 each represent a hydrogen atom or C1-6 alkyl which is optionally substituted by phenyl optionally substituted by C1-6 alkoxy; xe2x80x94Oxe2x80x94; or xe2x80x94Sxe2x80x94;
X and Z, which may be the same or different, represent CH or N;
R7 represents C1-6 alkyl, C1-6 alkoxy, a halogen atom, amino, nitro, hydroxyl, or an oxygen atom, which C1-6 alkyl and C1-6 alkoxy are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
R8 represents C1-6 alkyl, C1-6 alkoxy, a halogen atom, amino, nitro, or hydroxyl, which C1-6 alkyl and C1-6 alkoxy are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
Q represents  greater than Cxe2x95x90O,  greater than CHR13, or  greater than CHOR13 wherein R13 represents a hydrogen atom or C1-6 alkyl;
R9 represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or aralkyl, which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
R10 represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, or amino, which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl and which amino is optionally substituted by C1-6 alkyl, C1-6 alkoxycarbonyl, benzenesulfonyl in which the phenyl portion is optionally substituted by C1-6 alkyl, or benzyloxycarbonyl in which the phenyl portion is optionally substituted by C1-6 alkyl;
R11 represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, or amino, which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl and which amino is optionally substituted by carboxyl, sulfonyl, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylsulfonyl, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(CH2)uxe2x80x94R14 wherein u is an integer of 0 to 4 and R14 represents a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group, which carbocyclic group and heterocyclic group are optionally substituted by C1-6 alkyl, C1-6 alkoxy, phenyl optionally condensed with the carbocyclic or heterocyclic group, carboxyl, hydroxyl, nitro, amino, C1-6 alkylamino, or a halogen atom, or xe2x80x94S(xe2x95x90O)2xe2x80x94(CH2)vxe2x80x94R14 wherein v is an integer of 0 to 4 and R14 is as defined above;
R12 represents a hydrogen atom or C1-6 alkyl;
m is an integer of 0 to 5;
n is an integer of 0 to 4;
p is an integer of 1 to 3;
q is an integer of 1 to 3; and
r is 0 or 1.
The compounds according to the present invention are useful in the treatment of integrin xcex1vxcex23-mediated diseases, diseases where the inhibition of cell adhesion is of therapeutic benefit, and diseases where GP IIb/IIIa antagonistic action and/or platelet aggregation inhibitory action are of therapeutic benefit. The compounds according to the present invention are also useful as an agent for inhibiting platelet aggregation.
Compound
The terms xe2x80x9cC1-6 alkylxe2x80x9d and xe2x80x9cC1-6 alkoxyxe2x80x9d as used herein as a group or a part of a group mean straight chain, branched chain, or cyclic alkyl and alkoxy having 1 to 6, preferably 1 to 4 carbon atoms.
The terms xe2x80x9cC2-6 alkenylxe2x80x9d and xe2x80x9cC2-6 alkynylxe2x80x9d as used herein as a group or a part of a group mean straight chain, branched chain, or cyclic alkenyl and alkynyl having 2 to 6, preferably 2 to 4 carbon atoms.
Examples of C1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, n-hexyl, and cyclohexyl.
Examples of C1-6 alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.
Examples of C2-6 alkenyl include allyl.
Examples of C2-6 alkynyl include 2-propynyl and ethinyl.
Examples of xe2x80x9csaturated or unsaturated five- to seven-membered carbocyclic groupsxe2x80x9d include phenyl.
The term xe2x80x9csaturated or unsaturated five- to seven-membered heterocyclic ringxe2x80x9d as used herein means a five- to seven-membered heterocyclic ring containing at least one hetero-atom selected from oxygen, nitrogen, and sulfur atoms, preferably a five- to seven-membered heterocyclic ring containing one nitrogen atom, more preferably a five- or six-membered heterocyclic ring containing one nitrogen atom. The term xe2x80x9chetero-atomxe2x80x9d as used herein means an oxygen, nitrogen, or sulfur atom. Examples of saturated or unsaturated five- to seven-membered heterocyclic groups include pyrimidyl, 1,4,5,6-tetrahydropyrimidyl, imidazolyl, tetrahydro-[1,3]diazepinyl, and imidazolidinyl.
The saturated or unsaturated heterocyclic group may be condensed with other saturated or unsaturated heterocyclic ring to form a bicyclic ring. Such condensed cyclic groups include benzimidazolyl, naphthyl, and azabenzimidazolyl, for example, imidazo[4,5-b]pyridyl.
The term xe2x80x9caralkylxe2x80x9d as used herein as a group or a part of a group means a C1-6 alkyl, preferably C1-4 alkyl, substituted by a saturated or unsaturated five- to seven-membered carbocyclic group or heterocyclic group. Examples of aralkyls include benzyl and phenethyl.
The term xe2x80x9chalogen atomxe2x80x9d means a fluorine, chlorine, bromine, or iodine atom.
In preferred combinations of X with Z, X represents CH while Z represents N, or both X and Z represent N.
When D represents  greater than NR4, X preferably represents CH.
When D represents  greater than CR5R6, X preferably represents N.
When D represents xe2x80x94Oxe2x80x94, X preferably represents CH.
When D represents xe2x80x94Sxe2x80x94, X preferably represents CH.
D preferably represents  greater than NH or  greater than CH2.
The bicyclic heterocyclic group represented by A is preferably a nine- or ten-membered heterocyclic group, more preferably, a nine- or ten-membered heterocyclic group containing two or three nitrogen atoms.
Preferably, A represents a group represented by formula 
wherein
Het represents a saturated or unsaturated five- to seven-membered heterocyclic group containing two nitrogen atoms, which heterocyclic group is optionally condensed with other saturated or unsaturated five- to seven-membered carbocyclic ring or heterocyclic ring to form a bicyclic group, which heterocyclic group and bicyclic group are optionally substituted by C1-6 alkyl, amino, C1-6 alkoxy, C1-6 alkoxycarbonyl, or aralkyl, which C1-6 alkyl, amino, C1-6 alkoxy, C1-6 alkoxycarbonyl, and aralkyl are optionally substituted by C1-6 alkyl or C1-6 alkoxy.
More preferably, A represents a group of formula 
wherein
R21, R22, and R23, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, C2-6 alkenyl, or aralkyl, which C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxycarbonyl, C2-6 alkenyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl, or
R21 and R23 may together form
group xe2x80x94(CH2)4xe2x80x94,
group xe2x80x94(CH2)3xe2x80x94,
group xe2x80x94CHR24CH2CH2xe2x80x94 wherein R24 represents C1-6 alkyl or amino, which amino is optionally substituted by C1-6 alkyl, C1-6 alkoxycarbonyl, aralkyl, or aralkyloxycarbonyl,
group xe2x80x94CH2CHR24CH2xe2x80x94 wherein R24 is as defined above,
group xe2x80x94CH2CH2xe2x80x94,
group xe2x80x94CHR24CH2xe2x80x94 wherein R24 is as defined above,
group xe2x80x94CR25xe2x95x90CR26xe2x80x94 wherein R25 and R26, which may be the same or different, represent a hydrogen atom or C1-6 alkyl, or R25 and R26 may together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CR24xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 wherein R24 is as defined above, xe2x80x94CHxe2x95x90CR24xe2x80x94CHxe2x95x90CHxe2x80x94 wherein R24 is as defined above, xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, or
R21 and R23 may together form
xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94, or
xe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, and
R22 may represent a single bond between R21 and the nitrogen atom attached to R21.
In the compound represented by formula (I), one or more hydrogen atoms in the following portion may be substituted by R7. 
When m is zero (0), R7 is absent. When m is 1, one hydrogen atom in the above portion is substituted by R7. When m is 2 or more, two or more hydrogen atoms in the above portion are substituted by R7. In this case, the substituents may be the same or different. When R7 represents an oxygen atom, the bond between the R7 and the above portion is a double bond. m is preferably an integer of 0 to 2.
In the compound represented by formula (I), one or more hydrogen atoms in the phenylene portion may be substituted by R8.
When n is zero (0), R8 is absent. When n is 1, one hydrogen atom in the phenylene portion is substituted by R8. When n is 2 or more, two or more hydrogen atoms in the phenylene portion are substituted by R8. In this case, the substituents may be the same or different. n is preferably an integer of 0 to 2.
Q preferably represents  greater than Cxe2x95x90O or  greater than CH2.
R9 preferably represents a hydrogen atom, C1-6 alkyl, preferably methyl, propyl, or cyclopropylmethyl, or aralkyl, preferably benzyl or phenethyl.
R10 preferably represents a hydrogen atom, C2-6 alkynyl, or optionally substituted amino, more preferably a hydrogen atom or C2-6 alkynyl.
When r is zero (0), xe2x80x94(CHR10)rxe2x80x94 represents a single bond. r is preferably 1.
R11 preferably represents a hydrogen atom, C2-6 alkynyl, or optionally substituted amino, more preferably a hydrogen atom or optionally substituted amino.
A hydrogen atom(s) in amino represented by R11 may be substituted by two substituents which may be the same or different.
A preferred example of xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(CH2)uxe2x80x94R14 as a substituent for amino represented by R11 is a group wherein u is an integer of 0 to 3, more preferbly 0 or 1, and R14 represents a five- to seven-membered carbocyclic group, more preferably phenyl.
A preferred example of xe2x80x94S(xe2x95x90O)2xe2x80x94(CH2)vxe2x80x94R14 as a substituent for amino represented by R11 is a group wherein v is an integer of 0 to 3, more preferably 0 or 1, and R14 represents a five- to seven-membered carbocyclic group, more preferably phenyl.
Preferably, one or more hydrogen atoms in the carbocyclic group and the heterocyclic group represented by R14 are substituted by C1-6 alkyl, more preferably methyl, C1-6 alkoxy, more preferably methoxy, carboxyl, hydroxyl, nitro, amino, or a halogen atom.
The substituent for amino represented by R11 is preferably C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylsulfonyl, benzyloxycarbonyl in which the phenyl portion is optionally substituted by C1-6 alkyl, C1-6 alkoxy, carboxyl, hydroxyl, nitro, amino, or a halogen atom, or benzenesulfonyl in which the phenyl portion is optionally substituted by C1-6 alkyl, C1-6 alkoxy, carboxyl, hydroxyl, nitro, amino, or a halogen atom.
A group of preferred compounds represented by formula (I) are those wherein
A represents a group of formula 
xe2x80x83wherein
R21, R22, and R23 are as defined above;
D represents  greater than NH;
X represents CH;
Z represents N;
Q represents  greater than Cxe2x95x90O or  greater than CH2;
R9 represents a hydrogen atom, C1-6 alkyl, or aralkyl, which C1-6 alkyl and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
R10 represents a hydrogen atom or C2-6 alkynyl;
R11 represents a hydrogen atom or amino, which amino is optionally substituted by C1-6 alkyl; acetyl; C1-6 alkoxycarbonyl; C1-6 alkylsulfonyl; benzyloxycarbonyl in which the phenyl portion is optionally substituted; or benzenesulfonyl in which the phenyl portion is optionally substituted;
m and n each represent an integer of 0 to 2;
p is 2;
q is 1 or 2; and
r is 1; and
those wherein
A represents a group of formula 
xe2x80x83wherein
R21, R22, and R23 are as defined above;
D represents  greater than CH2;
X and Z both represent N;
Q represents  greater than Cxe2x95x90O or  greater than CH2;
R9 represents a hydrogen atom, C1-6 alkyl, or aralkyl, which C1-6 alkyl and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
R10 represents a hydrogen atom or C2-6 alkynyl;
R11 represents a hydrogen atom or amino, which amino is optionally substituted by C1-6 alkyl; acetyl; C1-6 alkoxycarbonyl; C1-6 alkylsulfonyl; benzyloxycarbonyl in which the phenyl portion is optionally substituted; or benzenesulfonyl in which the phenyl portion is optionally substituted;
m and n are each an integer of 0 to 2;
p is 2;
q is 1 or 2; and
r is 1.
Particularly preferred compounds represented by formula (I) are as follows:
1. t-butyl (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionate;
2. (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid;
3. (2S)-benzenesulfonylamino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoyl-amino]propionic acid;
4. t-butyl (2S)-benzenesulfonylamino-3-[4-{(3S)-(pyrimidin-2-ylamino)pyrrolidin-1-yl}benzoylamino]-propionate;
5. (2S)-benzenesulfonylamino-3-[4-{(3S)-(pyrimidin-2-ylamino)pyrrolidin-1-yl}benzoylamino]-propionic acid;
6. (2S)-benzenesulfonylamino-3-[4-{(3S)-(1,4,5,6-tetrahydropyrimidin-2-ylamino)pyrrolidin-1-yl}benzoylamino]propionic acid;
7. t-butyl (2S)-benzenesulfonylamino-3-[4-{(3R)-(pyrimidin-2-ylamino)pyrrolidin-1-yl}benzoylamino]-propionate;
8. (2S)-benzenesulfonylamino-3-[4-{(3R)-(pyrimidin-2-ylamino)pyrrolidin-1-yl}benzoylamino]-propionic acid;
9. t-butyl (2S)-benzenesulfonylamino-3-[4-{4-(1H-benzimidazol-2-ylamino)piperidin-1-yl}benzoylamino]-propionate;
10. (2S)-benzenesulfonylamino-3-[4-{4-(1H-benzimidazol-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
11. ethyl (3S)-[4-{4-(pyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]pent-4-ynate;
12. (3S)-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]pent-4-ynic acid;
13. t-butyl (2S)-(benzyloxycarbonyl)amino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionate;
14. (2S)-(benzyloxycarbonyl)amino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
15. (2S)-amino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
16. (2S)-(benzyloxycarbonyl)amino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
17. (2S)-butane-1-sulfonylamino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoyl-amino]propionic acid;
18. t-butyl (2S)-benzenesulfonylamino-3-[N-(cyclopropylmethyl)-N-[4-{4-(pyrimidin-2-ylamino)-piperidin-1-yl}benzoyl]amino]propionate;
19. (2S)-benzenesulfonylamino-3-[N-(cyclopropylmethyl)-N-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoyl]amino]propionic acid;
20. (2S)-benzenesulfonylamino-3-[N-(cyclopropylmethyl)-N-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-piperidin-1-yl}benzoyl]amino]propionic acid;
21. t-butyl (2S)-benzenesulfonylamino-3-{4-(4-guanidinopiperidin-1-yl)benzoylamino}propionate;
22. (2S)-benzenesulfonylamino-3-{4-(4-guanidinopiperidin-1-yl)benzoylamino}propionic acid;
23. t-butyl 3-[4-{4-(1H-benzimidazol-2-ylamino)-piperidin-1-yl}benzoylamino]-(2S)-{(benzyloxycarbonyl)-amino}propionate;
24. 3-[4-{4-(1H-benzimidazol-2-ylamino)-piperidin-1-yl}benzoylamino]-(2S)-{(benzyloxycarbonyl)-amino}propionic acid;
25. t-butyl (2S)-(benzyloxycarbonyl)amino-3-[4-[4-{(1-t-butoxycarbonyl-1H-benzimidazol-2-yl)amino}piperidin-1-yl]benzoylamino]propionate;
26. t-butyl (2S)-amino-3-[4-[4-{(1-t-butoxy-carbonyl-1H-benzimidazol-2-yl)amino}piperidin-1-yl]-benzoylamino]propionate;
27. t-butyl (2S)-(butane-1-sulfonylamino)-3-[4-[4-{(1-t-butoxycarbonyl-1H-benzimidazol-2-yl)amino}-piperidin-1-yl]benzoylamino]propionate;
28. (2S)-butane-1-sulfonylamino-3-[4-{4-(1H-benzimidazol-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
29. (2S)-amino-3-[4-{4-(1H-benzimidazol-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid;
30. t-butyl 3-[4-[4-{(1-t-butoxycarbonyl-1H-benz-imidazol-2-yl)amino}piperidin-1-yl]benzoylamino]-(2S)-{(2,4,6-trimethylbenzenesulfonyl)amino}propionate;
31. 3-[4-{4-(1H-benzimidazol-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(2,4,6-trimethylbenzene-sulfonyl)amino}propionic acid;
32. t-butyl 3-[4-[4-{(1-t-butoxycarbonyl-1H-benz-imidazol-2-yl)amino}piperidin-1-yl]benzoylamino]-(2S)-{(4-fluorobenzenesulfonyl)amino}propionate;
33. 3-[4-{4-(1H-benzimidazol-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-fluorobenzenesulfonyl)-amino}propionic acid;
34. t-butyl 3-[4-[4-{(1-t-butoxycarbonyl-1H-benzimidazol-2-yl)amino}piperidin-1-yl]benzoylamino]-(2S)-{(4-nitrobenzenesulfonyl)amino}propionate;
35. 3-[4-{4-(1H-benzimidazol-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-nitrobenzenesulfonyl)amino}-propionic acid;
36. (2S)-(4-aminobenzenesulfonyl)amino-3-[4-{4-(1H-benzimidazol-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
37. t-butyl (2S)-benzenesulfonylamino-3-[4-[4-{(1H-imidazo[4,5-b]pyridin-2-yl)amino}piperidin-1-yl]benzoylamino]propionate;
38. (2S)-benzenesulfonylamino-3-[4-[4-{(1H-imidazo[4,5-b]pyridin-2-yl)amino}piperidin-1-yl]benzoyl-amino]propionic acid;
39. t-butyl (2S)-benzenesulfonylamino-3-[4-[4-[{4,5-dihydro-1-(4-methoxybenzyl)-1H-imidazol-2-yl}-amino]piperidin-1-yl]benzoylamino]propionate;
40. (2S)-benzenesulfonylamino-3-[4-{4-(4,5-dihydro-1H-imidazol-2-ylamino)piperidin-1-yl}benzoyl-amino]propionic acid;
41. t-butyl (2S)-benzenesulfonylamino-3-[4-{4(4,5,6,7-tetrahydro-1H-[1,3]diazepin-2-ylamino)-piperidin-1-yl}benzoylamino]propionate;
42. (2S)-benzenesulfonylamino-3-[4-{4-(4,5,6,7-tetrahydro-1H-[1,3]diazepin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
43. t-butyl (2S)-benzenesulfonylamino-3-[4-[4-[{N-methyl-N-(pyrimidin-2-yl)}amino]piperidin-1-yl]-benzoylamino]propionate;
44. (2S)-benzenesulfonylamino-3-[4-[4-[{N-methyl-N-(pyrimidin-2-yl)}amino]piperidin-1-yl]benzoylamino]-propionic acid;
45. (2S)-benzenesulfonylamino-3-[4-[4-[{N-methyl-N-(1,4,5,6-tetrahydropyrimidin-2-yl)}amino]piperidin-1-yl]benzoylamino]propionic acid;
46. t-butyl (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzylamino]-propionate;
47. (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-ylamino )piperidin-1-yl}benzylamino]propionic acid;
48. (2S)-benzenesulfonylamino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzyl-amino]propionic acid;
49. (2S)-benzenesulfonylamino-3-[N-benzyl-N-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzyl]amino]propionic acid;
50. t-butyl (2S)-benzenesulfonylamino-3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoyl-amino]propionate;
51. (2S)-benzenesulfonylamino-3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
52. (2S)-benzenesulfonylamino-3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
53. t-butyl (2S)-benzenesulfonylamino-3-[3-fluoro-4-{4-(4,5-dihydro-1H-imidazol-2-ylamino)-piperidin-1-yl}benzoylamino]propionate;
54. (2S)-benzenesulfonylamino-3-[3-fluoro-4-{4-(4,5-dihydro-1H-imidazol-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
55. t-butyl (2S)-benzenesulfonylamino-3-[2,3-difluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionate;
56. (2S)-benzenesulfonylamino-3-[2,3-difluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
57. (2S)-benzenesulfonylamino-3-[2,3-difluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid;
58. t-butyl (2S)-benzenesulfonylamino-3-[3-chloro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoyl-amino]propionate;
59. (2S)-benzenesulfonylamino-3-[3-chloro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
60. (2S)-benzenesulfonylamino-3-[3-chloro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
61. t-butyl 2-(N-benzenesulfonyl-N-methyl)-amino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionate;
62. 2-(N-benzenesulfonyl-N-methyl)amino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
63. 2-(N-benzenesulfonyl-N-methyl)amino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
64. t-butyl (2S)-(benzyloxycarbonyl)amino-3-[3-fluoro-4-[4-[{N-(1,4,5,6-tetrahydropyrimidin-2-yl)-N-(4-methoxybenzyl)}amino]piperidin-1-yl]benzoylamino]-propionate;
65. t-butyl (2S)-amino-3-[3-fluoro-4-[4-[{N-(1,4,5,6-tetrahydropyrimidin-2-yl)-N-(4-methoxybenzyl)}-amino]piperidin-1-yl]benzoylamino]propionate;
66. t-butyl 3-[3-fluoro-4-[4-[[N-{1,4,5,6-tetrahydropyrimidin-2-yl)-N-(4-methoxybenzyl)}amino]-piperidin-1-yl]benzoylamino]-(2S)-{(4-nitrobenzenesulfonyl)amino}propionate;
67. 3-[3-fluoro-4-{4-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-nitrobenzenesulfonyl)amino}propionic acid;
68. (2S)-(4-aminobenzenesulfonyl)amino-3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]propionic acid;
69. t-butyl (2S)-(benzyloxycarbonyl)amino-3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoyl-amino]propionate;
70. t-butyl (2S)-amino-3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionate;
71. t-butyl 3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-methoxy-benzenesulfonyl)amino}propionate;
72. 3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]-(2S)-{(4-methoxybenzene-sulfonyl)amino}propionic acid;
73. 3-[3-fluoro-4-{4-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-methoxybenzenesulfonyl)amino}propionic acid;
74. 3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]-(2S)-{(4-hydroxybenzene-sulfonyl)amino}propionic acid;
75. 3-[3-fluoro-4-{4-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-hydroxybenzenesulfonyl)amino}propionic acid;
76. t-butyl (2S)-(4-carboxybenzenesulfonyl)-amino-3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionate;
77. (2S)-(4-carboxybenzenesulfonyl)amino-3-[3-fluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoyl-amino]propionic acid;
78. (2S)-(4-carboxybenzenesulfonyl)amino-3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]propionic acid;
79. t-butyl (2S)-acetamido-3-[3-fluoro-4-[4-[{N-(1,4,5,6-tetrahydropyrimidin-2-yl)-N-(4-methoxy-benzyl)}amino]piperidin-1-yl]benzoylamino]propionate;
80. (2S)-acetamido-3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoyl-amino]propionic acid;
81. t-butyl (2S)-(benzyloxycarbonyl)amino-3-[2,3-difluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionate;
82. t-butyl (2S)-amino-3-[2,3-difluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionate;
83. t-butyl 3-[2,3-difluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-methoxy-benzenesulfonyl)amino}propionate;
84. 3-[2,3-difluoro-4-{4-(pyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]-(2S)-{(4-hydroxybenzene-sulfonyl)amino}propionic acid;
85. 3-[2,3-difluoro-4-{4-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-(2S)-{(4-hydroxybenzenesulfonyl)amino}propionic acid;
86. t-butyl (2S)-(4-carboxybenzenesulfonyl)-amino-3-[2,3-difluoro-4-{4-(pyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]propionate;
87. (2S)-(4-carboxybenzenesulfonyl)amino-3-[2,3-difluoro-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
88. (2S)-(4-carboxybenzenesulfonyl)amino-3-[2,3-difluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]propionic acid;
89. t-butyl (2S)-benzenesulfonylamino-3-[4-{4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl}benzoyl-amino]propionate;
90. (2S)-benzenesulfonylamino-3-[4-{4-(1H-benz-imidazol-2-ylmethyl)piperazin-1-yl}benzoylamino]-propionic acid;
91. t-butyl (2S)-benzenesulfonylamino-3-[3-methoxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionate;
92. (2S)-benzenesulfonylamino-3-[3-methoxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
93. (2S)-benzenesulfonylamino-3-[3-methoxy-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid;
94. (2S)-benzenesulfonylamino-3-[3-hydroxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionic acid;
95. (2S)-benzenesulfonylamino-3-[3-hydroxy-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
96. t-butyl (2S)-(benzyloxycarbonyl)amino-3-[3-methoxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionate;
97. t-butyl (2S)-amino-3-[3-methoxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionate;
98. t-butyl (2S)-(4-methoxybenzenesulfonyl)-amino-3-[3-methoxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionate;
99. (2S)-(4-hydroxybenzenesulfonyl)amino-3-[3-hydroxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
100. (2S)-(4-hydroxybenzenesulfonyl)amino-3-[3-hydroxy-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]propionic acid;
101. t-butyl (2S)-(4-carboxybenzenesulfonyl)-amino-3-[3-methoxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionate;
102. (2S)-(4-carboxybenzenesulfonyl)amino-3-[3-methoxy-4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}-benzoylamino]propionic acid;
103. (2S)-(4-carboxybenzenesulfonyl)amino-3-[3-methoxy-4-{4-(1,4,5,6-tetrahydropyrimidin-2-ylamino)-piperidin-1-yl}benzoylamino]propionic acid;
104. t-butyl (2S)-amino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionate; and
105. methyl (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]-propionate.
The compounds according to the present invention may form pharmacologically acceptable salts thereof. Such salts include non-toxic salts. Preferred salts include: hydrohalogenic acid salts such as hydrochloride salts, hydrobromide salts, or hydroiodide salts; inorganic acid salts such as nitric acid salts, perchloric acid salts, sulfuric acid salts, or phosphoric acid salts; lower alkylsulfonic acid salts such as methanesulfonic acid salts, trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts; arylsulfonic acid salts such as benzenesulfonic acid salts or p-toluenesulfonic acid salts; organic acid salts such as fumaric acid salts, succinic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, or maleic acid salts; amino acid salts such as glutamic acid salts or aspartic acid salts; alkali metal or alkaline earth metal salts such as sodium salts, potassium salts, and calcium salts; and organic alkali salts such as pyridine salts or triethylamine salts.
The compounds according to the present invention may form solvates (for example, hydrates or ethanolate).
Production of compounds
Compounds represented by formula (I), wherein X represents CH and Z represents N. may be produced according to the following scheme: 
 less than Step 1 greater than 
An optionally substituted ethyl 4-fluorobenzoate may be reacted with 4-hydroxypiperidine or 3-pyrrolidinol which is optionally substituted at the carbon atom(s) (a piperidine derivative) in the presence of a reaction solvent, such as dimethyl sulfoxide, sulfolane, or butanol, preferably dimethyl sulfoxide, at 50xc2x0 C. to 180xc2x0 C., preferably 80xc2x0 C. to 140xc2x0 C., to prepare a compound represented by formula (II). In this reaction, an organic base such as diisopropylethylamine or an inorganic salt such as ammonium chloride may be added as an acid scavenger.
In addition to ethyl 4-fluorobenzoate, other ester compounds, for example, methyl, propyl, butyl, or benzyl ester compounds, may be used as the starting compound.
Further, in addition to ethyl 4-fluorobenzoate, other 4-halogenobenzoates which have been substituted at the 4-position, for example, ethyl 4-iodobenzoate and ethyl 4-bromobenzoate, may be used. Among them, the use of ethyl 4-fluorobenzoate is preferred from the viewpoint of yield.
Furthermore, in addition to ethyl 4-fluorobenzoate, optionally substituted 4-fluorobenzonitrile may be used as a starting compound. In this case, in a proper later step, for example, acid hydrolysis or the like may be performed for conversion to a free carboxyl group, thereby producing a compound represented by formula (VI).
An aminopiperidine of which the primary amine is optionally protected, for example, 4-aminopiperidine, may also be used as the piperidine derivative. The use of the aminopiperidine derivative is advantageous in that the step of introducing the amino group (step 2) may be omitted.
Alternatively, the compound represented by formula (II) may be produced by reacting ethyl 4-bromobenzoate with a piperidine derivative in the presence of palladium, a phosphine ligand, and a base. Phosphine ligands usable herein include 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, bis(diphenylphosphino)propane, bis(diphenylphosphino)ferrocene, tri-t-butylphosphine, tri-o-tolylphosphine, and triphenylphosphine. Among them, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl is preferred. Bases include sodium t-butoxide, cesium carbonate, potassium carbonate, and triethylamine. Among them, sodium t-butoxide is preferred. Piperidines include hydroxypiperidine, pyrrolidinol, azetidinol, azepanol, and azocanol.
 less than Step 2 greater than 
The compound represented by formula (II) may be reacted with phthalimide and an azo compound in a reaction solvent such as tetrahydrofuran, benzene, toluene, dioxane, or dimethylformamide, preferably tetrahydrofuran, in the presence of a trialkylphosphine, preferably tributylphosphine, at xe2x88x9240xc2x0 C. to 100xc2x0 C., preferably xe2x88x9210xc2x0 C. to 40xc2x0 C., followed by the removal of the phthaloyl group to produce a compound represented by formula (III). Azo compounds include 1,1xe2x80x2-(azodicarbonyl)dipiperidine, diethyl azodicarboxylate, and 1,1xe2x80x2-azobis(N,N-dimethylformamide). Among them, 1,1xe2x80x2-(azodicarbonyl)dipiperidine is preferred.
Alternatively, the compound represented by formula (III) may be produced by converting the hydroxyl group in the compound represented by formula (II) to a leaving group, for example, a sulfonyloxy group such as a methanesulfonyloxy group, or a halogen atom such as a bromine atom, allowing sodium azide or a combination of hydrazoic acid with an azo compound to act on the leaving group to convert the leaving group to an azide group, and then reducing the azide group. See intermediates 35, 36, 41, 42, 43, 47, 48, 49, and 58.
 less than Step 3 greater than 
Group A may be introduced into the free primary amine in the compound represented by formula (III) to produce a compound represented by formula (IV). The Nxe2x80x94C bond between the compound represented by formula (III) and group A may be formed by reacting the compound represented by formula (III) with a reagent, such as optionally modified or substituted 2-bromopyrimidine, modified or substituted 2-chlorobenzimidazole, or 2-methylthio-2-imidazoline, in the presence of a reaction solvent, such as dimethylformamide, dimethyl sulfoxide, sulfolane, pyridine, or methanol, preferably dimethylformamide, at 50xc2x0 C. to 170xc2x0 C., preferably 60xc2x0 C. to 140xc2x0 C.
Reagents usable in this step is not limited to those recited herein, and any reagent may be used so far as a carbon atom attached to two nitrogen atoms finally combines with the nitrogen atom in the primary amine attached to a carbon atom in the piperidine derivative to form a single bond. Further, optimization of the kind of substrates used and reaction conditions permits the Nxe2x80x94C bond to be formed by reacting palladium having a valency of 0 (zero), a phosphine ligand, and a base. Furthermore, the Nxe2x80x94C bond may be formed in accordance with the method of Tetrahedron, 51(2), 353, 1995. See intermediates 26, 27, 29, and 39.
An organic base, such as diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, or triethylamine, is preferably added as an acid scavenger from the viewpoint of improving the yield. The addition of 2 to 10 equivalents of diisopropylethylamine is preferred.
A compound represented by formula (IV) wherein R4 is substituted may be prepared by conventional or reductive N-alkylation followed by the introduction of group A into the primary amino group in the compound represented by formula (III), or alternatively the introduction of group A into the primary amino group in the compound represented by formula (III) followed by N-alkylation of the secondary amino group. See intermediate 30.
Alternatively, the compound represented by formula (IV) may be produced by suitably oxidizing a hydroxyl group in the piperidine derivative portion of the compound represented by formula (II) to give a ketone which is then reductively aminated with an amino-containing compound (a compound corresponding to group A), for example, 2-aminopyrimidine.
The compound represented by formula (IV) may also be produced by reacting a compound that is previously prepared by attaching a basic functional group corresponding to group A, for example, pyrimidine or benzimidazole, to a primary amino group in an aminopiperidine, with ethyl 4-fluorobenzoate. See intermediates 16, 17, 18, 23, 24, and 25.
 less than Step 4 greater than 
The carboxylic ester represented by formula (IV) may be hydrolyzed, followed by the formation of an amide bond to produce a compound represented by formula (V). More specifically, a free carboxyl group prepared by hydrolysis with an alkali according to a conventional method is reacted with an amine represented by formula
R9HNCHR10CHR11COOR12
wherein R9, R10, R11, and R12 are as defined in formula (I), to perform condensation reaction, thereby producing the amide compound represented by formula (V).
Among the compounds represented by formula (V), compounds having an optionally substituted pyrimidine ring may be, if necessary, reduced to a corresponding tetrahydropyrimidine.
In the condensation reaction, a condensing agent, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, may be used either solely or in combination with a peptide synthesis reagent, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, or benzotriazol-1-yloxytri(dimethylamino)phosphonium hexafluorophosphate. The combination of these reagents permits the desired condensation reaction to proceed with high efficiency. The use of a combination of 1 to 3 equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride with 1 to 2 equivalents of 1-hydroxybenzotriazole is preferred from the viewpoint of optimizing the yield.
Reaction solvents usable in the condensation reaction include dimethylformamide, dioxane, and tetrahydrofuran. Among them, dimethylformamide is preferred. The reaction may be carried out at 0xc2x0 C. to 80xc2x0 C., preferably 20xc2x0 C. to 60xc2x0 C.
In the condensation reaction, a tertiary amine, such as diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, or triethylamine, may be added as an organic base from the viewpoint of improving the yield. Among these tertiary amines, N-methylmorpholine is preferably added in an amount of 2 to 10 equivalents.
The compound represented by formula (V), wherein  greater than Cxe2x95x90O attached to the phenylene portion is  greater than CH2, may be produced by reducing a carboxylic ester in the compound represented by formula (IV) to convert the carboxylic ester to an aldehyde group and then reductively reacting the resulting compound with an amine represented by formula
R9HNCHR10CHR11COOR12
wherein R9, R10, R11, and R12 are as defined above in connection with formula (I). See Example 46.
The compounds represented by formula (V) prepared by the reductive amination wherein R9 represents a group other than the hydrogen atom may be produced by the step of reaction other than described above. Specifically, the free aldehyde group may be reductively reacted with an amine represented by formula
H2NCHR10CHR11COOR12
wherein R10, R11, and R12 are as defined in formula (I), to produce a compound of formula (V) wherein R9 represents a hydrogen atom. Thereafter, the product may be further reacted by reductive amination to introduce an alkyl, alkenyl, or aralkyl group into R9. The introduction of the alkyl, alkenyl, or aralkyl group into R9 is not always carried out only for the compound represented by formula (V) in the scheme. Specifically, the introduction of the alkyl, alkenyl, or aralkyl group into R9 may be carried out for the compound represented by formula (VI) in the scheme. See Example 49.
In this reaction, R12 in xe2x80x94COOR12 corresponding to the carboxylic ester portion of the amine may be a hydrogen atom.
 less than Step 5 greater than 
The carboxylic ester portion in the compound represented by formula (V) in the scheme may be optionally converted to a free carboxyl group to produce the compound represented by formula (VI).
The carboxylic ester portion in the compound represented by formula (V) may be converted to the intended free carboxyl group by a conventional method, for example, by hydrolysis with an alkali, hydrolysis with an acid, or reaction with an acid. The deesterification reaction may be achieved by a novel method without any restriction or limitation.
The compound represented by formula (V) as such is integrin xcex1vxcex23 antagonist and/or GP IIb/IIIa antagonist that can be orally administered. Therefore, the step of converting the carboxylic ester to the free carboxyl group is not always necessary.
Among the compounds represented by formula (VI), compounds having an optionally substituted pyrimidine ring may be optionally reduced to a corresponding tetrahydropyrimidine. The reduction may be carried out by a conventional method. Examples of reduction methods usable herein include catalytic reduction in the presence of a catalyst, such as palladium-carbon, ruthenium-carbon, rhodium-carbon, palladium oxide, platinum oxide, ruthenium oxide, rhodium platinum oxide complex, rhodium aluminum oxide complex, Raney nickel, or palladium black, and a reaction, for example, with metallic sodium or metallic lithium in liquid ammonia. Preferably, the reduction is carried out in an acidic solvent, for example, in acetic acid acidified with hydrochloric acid, in the presence of palladium-carbon with hydrogen under normal or applied pressure.
 less than Steps 6, 7, and 8 greater than 
The compound represented by formula (VII) may be produced by previously protecting the primary amine in the piperidine derivative portion of the compound represented by formula (III), converting the benzoic ester portion to a free carboxyl group, and reacting the carboxyl group with an amine represented by formula
R9HNCHR10CHR11COOR12
wherein R9, R10, R11, and R12 are as defined above in connection with formula (I), to form an amide bond. In the compound represented by formula (VII), R31 represents a protective group of the amino group. Protective groups usable for the amino group include t-butyloxycarbonyl, benzyloxycarbonyl, and p-methoxybenzyloxycarbonyl. Among them, t-butyloxycarbonyl is preferred.
Next, the protective group in the piperidine derivative portion may be removed, if necessary, followed by conversion of the carboxylic ester portion to a free carboxyl group, thereby producing a compound represented by formula (VIII).
The compound represented by formula (VI) may be produced by introducing a basic functional group corresponding to group A, for example, a pyrimidine, benzimidazole, or amidino group, into the deprotected primary amine according to step 3, and then optionally converting the carboxylic ester portion to a free carboxyl group. See intermediates 20, 21, and 22 and Examples 21 and 22.
In the scheme, for example, the compound represented by formula (IV) is first converted to the compound represented by formula (V) to form an amide bond, followed by reduction of an optionally substituted pyrimidine ring in the compound represented by formula (VI). However, for example, a basic functional group, for example, an optionally substituted pyrimidine ring, bonded to the primary amino group of the piperidine derivative among the compounds represented by formula (IV) may be reduced followed by amide bond formation.
In the compounds represented by formulae (V) and (VI) in the scheme, atomic groups, which have been constructed in the molecule, for example, R7, R8, R9, R10, and R11, may be optionally converted. Regarding the conversion of R11 in the compound represented by formula (VI), for example, reference may be made to Examples 15, 16, 17, 26, 27, 30, 32, 34, 36, 61, 65, 66, 68, 70, 71, 74, 76, 79, 82, 83, 84, 86, 97, 98, 99, 101, and 104.
The compound represented by formula (I), wherein both X and Z represent N, may be produced according to steps 3 to 5, using the corresponding phenyl piperazine derivative represented by formula (III) as a starting compound. The corresponding phenylpiperazine derivative represented by formula (III) may be produced, for example, by reacting piperazine with ethyl 4-fluorobenzoate in dimethyl sulfoxide at 120xc2x0 C. according to step 1.
The compound represented by formula (I), wherein X represents N and Z represents CH, may be produced from 4-bromobenzyl alcohol with a protected hydroxyl group according to the method described in WO 94/12181. More specifically, the phenylpiperidine derivative corresponding to formula (II) may be produced by reacting 4-bromobenzyl alcohol with lithium introduced thereinto (with a protected hydroxyl group) with N-Boc-4-piperidone to prepare a phenylpiperidine derivative, reductively removing the resultant hydroxyl group, deprotecting the protected hydroxyl group, esterifying the deprotected hydroxyl group, and removing the Boc group. The compound represented by formula (I), wherein X represents N and Z represents CH, may be produced from this phenylpiperidine derivative through steps 2 to 5.
The compound represented by formula (I), wherein D represents  greater than CR5R6, may be produced according to steps 4 and 5, using as a starting compound a compound represented by formula (IV) wherein the group corresponding to D in formula (I) represents  greater than CR5R6. The compound represented by formula (IV), wherein the group corresponding to D in formula (I) represents  greater than CR5R6, may be produced, for example, by reacting 2-(chloromethyl)benzimidazole with ethyl 4-(piperazin-1-yl)benzoate in dimethyl sulfoxide in the presence of potassium carbonate at room temperature. See Examples 89 and 90.
The compound represented by formula (I), wherein D represents xe2x80x94Oxe2x80x94, may be produced according to steps 4 and 5, using as a starting compound a compound represented by formula (IV) wherein the group corresponding to D in formula (I) represents xe2x80x94Oxe2x80x94. The compound represented by formula (IV), wherein the group corresponding to D in formula (I) represents xe2x80x94Oxe2x80x94, may be produced by reacting the hydroxyl group in the compound represented by formula (II) with a basic functional group having an alkylsulfonyl group, that is, a compound corresponding to group A. This reaction may be carried out in accordance with the method described, for example, in Japanese Patent Laid-Open No. 97818/1993 and EP 468766A1.
The compound represented by formula (I), wherein D represents xe2x80x94Sxe2x80x94, may be produced according to steps 4 and 5, using as a starting compound a compound represented by formula (IV) wherein the group corresponding to D in formula (I) represents xe2x80x94Sxe2x80x94. The compound represented by formula (IV), wherein the group corresponding to D in formula (I) represents xe2x80x94Sxe2x80x94, may be produced by halogenating the hydroxyl group in the compound represented by formula (II) and reacting the halogen atom with a basic functional group having group xe2x80x94SH, that is, a compound corresponding to group A. The reaction of the halogen atom with group xe2x80x94SH may be carried out in accordance with the method described, for example, in Res. Lab., Kohjin Co., Ltd., Japan Chem. Pharm. Bull. (1977), 25(10), 2624-37.
Use of compounds/pharmaceutical composition
The compounds according to the present invention have potent integrin xcex1vxcex23 antagonistic activity, as demonstrated in Pharmacological Test Example 1. Accordingly, the compounds according to the present invention may be used in the treatment of integrin xcex1vxcex23-mediated diseases. The integrin xcex1vxcex23 mediates cardiovascular diseases such as acute myocardial infarction, neointima formation hypertrophy, restenosis after PTCA/stent operation, unstable angina, acute coronary syndrome, angina pectoris after PTCA/stent operation, arterial sclerosis, particularly atherosclerosis; angiogenesis-related diseases such as diabetic retinopathy, diabetic vascular complication, or vascular grafting; cerebrovascular diseases such as cerebral infarction; cancers such as solid tumors or metastasis thereof, immunological diseases such as arthritis, particularly rheumatic arthritis; and osteopathy such as osteoporosis, hypercalcemia, periodontitis, hyperparathyroidism, periarticular sore, or Paget""s diseases (DN and P, 10 (8), 456 (1997)). The term xe2x80x9ctherapyxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes xe2x80x9cpreventionxe2x80x9d or xe2x80x9cprophylaxis.xe2x80x9d
The compounds according to the present invention have cell adhesion inhibitory activity, as demonstrated in Pharmacological Test Example 3. Accordingly, the compounds according to the present invention may be used in the treatment of diseases where the inhibition of cell adhesion is of therapeutic benefit. More specifically, such diseases as cardiovascular diseases, angiogenesis-related diseases, cerebrovascular diseases, cancers, and immunological diseases can be treated by inhibiting adhesion between smooth muscule cells and cell adherent proteins, particularly vitronectin (DN and P, 10 (8), 456 (1997)). Further, cancers or metastasis thereof can be treated by inhibiting adhesion between vascular endothelial cells and cell adherent proteins, particularly vitronectin. Furthermore, osteopathy can be treated by inhibiting adhesion between osteoclasts and cell adherent proteins, particularly osteopontin.
The term xe2x80x9ccell adhesionxe2x80x9d as used herein means adhesion between vascular cells, specifically smooth muscle cells and endothelial cells, and cell adherent proteins, specifically vitronectin, osteopontin, and von Willebrand factors, adhesion between vascular cells and hemocyte cells, specifically leukocyte, and adhesion between hemocyte cells themselves, particularly adhesion between human vascular smooth muscle cells and human vitronectin.
As described in Pharmacological Test Example 2, the compounds according to the present invention have GP IIb/IIIa antagonistic activity and human platelet aggregation inhibitory activity. Therefore, the compounds according to the present invention can be used in the treatment of diseases where GP IIb/IIIa antagonism and the inhibition of human platelet aggregation are of therapeutic benefit. More specifically, the compounds according to the present invention can be used in the treatment of platelet thrombosis and thromboembolism during and after the treatment of thrombolysis and after angioplasty of coronary artery and other arteries and after bypassing of coronary artery, the improvement of peripheral circulating blood stream, and the inhibition of blood clotting during extracorporeal circulation. Furthermore, the compounds according to the present invention can be used in the treatment of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (Gendai Iryo, 29, (11), 2753 (1997)).
Not only compounds represented by formula (I) wherein R12 represents an alkyl group, but also compounds represented by formula (I) wherein R12 represents a hydrogen atom, for example, a compound prepared in Example 59, had oral absorption in rats (data not shown). Therefore, any of the compounds, wherein R12 represents an alkyl group or a hydrogen atom, can be used in the treatment of the above diseases.
The compounds according to the present invention and pharmacologically acceptable salts and solvates thereof can be administered orally or parenterally by administration routes, for example, inhalation administration, rhinenchysis, instillation, subcutaneous administration, intravenous injection, intravenous drip infusion, intramuscular injection, rectal administration, or percutaneous administration, and thus may be formed into appropriate various dosage forms depending on oral or parenteral administration routes and administered to human and non-human animals.
The compounds according to the present invention may be formulated into, for example, oral preparation, such as tablets, capsules, granules, powders, pills, particulates, troches, syrups, or emulsions; liquids for external use such as inhalants, nasal drops, or eye drops; injections such as intravenous injections or intramuscular injections; intravenous drip infusions; preparations for rectal administrations; oleaginous suppositories; water-soluble suppositories; and liniments such as ointments depending upon applications thereof.
These various preparations may be prepared by conventional methods with commonly used components, for example, excipients, extenders, binders, humidifiers, disintegrants, surface active agents, lubricants, dispersants, buffers, preservatives, dissolution aids, antiseptics, flavoring agents, analgesic agents, stabilizers and the like. Non-toxic additives usable herein include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, olive oil, propylene glycol, polyethylene glycol, syrup, petrolatum, glycerin, ethanol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, ascorbic acid, and cyclodextrins.
The content of the compound according to the present invention in the medicament may vary according to the dosage form. In general, however, the content is generally 1 to 70% by weight, preferably 5 to 50% by weight, based on the whole composition. The dose for the treatment and prevention of coronary diseases and the like may be appropriately determined in consideration of, for example, the dosage route and the age, sex and severity of condition of patients, and the preparation may be administered usually in an amount of about 0.1 to 2,000 mg, preferably about 5 to 400 mg per day per adult. This dose is administered at a time daily, divided doses of several times daily, or at a time every several days.